Currently, there are no effective therapies for relapsing, metastatic or androgen-independent prostate cancers;appropriate intervention would be greatly enhanced with specific monitoring of wide spread micro-disease. Blood PSA (Prostate Specific Antigen) screening and digital rectal exams can detect early warning signs of prostate cancer but an effective tissue-specific method for spatial localization of metastatic disease is not available. Human prostate specific membrane antigen (PSMA) is an integral trans-membrane protein, associated with the prostate epithelium, prostatic tumor cells and the neovasculature of other tumor types. PSMA is a 750 amino acid type II glycoprotein that is up-regulated in prostate cancer, including metastatic disease, which exhibits hydrolytic activity on neuro-peptides. The enzymatic aspect of PSMA is a unique exopeptidase with reactivity toward poly-gamma-glutamated folates, capable of sequentially removing the poly-gamma-glutamyl termini. Since PSMA is expressed by virtually all prostate cancers and especially poorly differentiated, metastatic and hormone-refractory carcinomas, it is a very attractive target for prostate cancer imaging and therapy. A range of PSMA inhibitors have been reported that may serve as platforms for the development of agents targeted to PSMA enzymatic activity. In a successfully completed phase 1 SBIR award (1R43EB004253), Molecular Insight Pharmaceuticals has developed novel Iodine-123 radiolabeled inhibitors that target PSMA and may provide specific diagnostic and special localization of metastases of prostate cancer. In vitro PSMA cell binding assays and in vivo distribution studies culminated in an exploratory Investigative new drug application (IND) to the FDA to evaluate these compounds as metastatic prostate cancer imaging agents in humans. Exceptional tumor accumulation was observed in previously identified prostate metastasis along with localization of previously unknown disease. Molecular Insight Pharmaceuticals is completing pre-clinical safety assessments and CMC developments for the diagnostic agent, 123IMIP-1072. Additional human studies have begun to examine healthy male subjects with normal prostates and to compare imaging in confirmed prostate cancer patients using Indium-111 ProstaScint. The goal of this phase 1 SBIR application is to obtain pre-clinical data on the iodine-131 labeled therapeutic version of MIP-1072 and establish its potential to target PSMA expressing tumors. Prostate cancer cellular binding studies, in vivo organ distributions studies in rats and tumor bearing mice along with treatment efficacy studies in a nude mouse model of prostate cancer will be performed and summarized to request a clinical development meeting with the FDA. PUBLIC HEALTH RELEVANCE: Determination of serum prostate specific antigen (PSA) is an effective early screen for potential prostate cancer with revenues estimated at over $350 million annually. Although the current screening method of PSA levels in the blood is valuable for early detection, the confirmation by fine needle biopsy does not give a representative evaluation of the entire prostate or determine lymph node involvement. A reliable method for non-invasive diagnosis and monitoring of primary and metastatic tumors would be an important addition to the management of prostate cancer patients. Molecular Insight Pharmaceuticals has identified a novel new iodinated compound targeted to Prostrate Specific Membrane Antigen (PSMA) that shows considerable promise as diagnostic molecular imaging agent to monitor metastatic prostate cancer. Currently there are no approved or even promising therapeutic agents for this advance stage of cancer. Replacing the diagnostic isotope (iodine-123) with the radio-therapeutic isotope (iodine-131) could offer hope of treatment to this population. About 28,000 American men die each year of this disease and an effective treatment would meet a large area of unmet clinical need. In a successfully completed phase 1 SBIR award (1R43EB004253), Molecular Insight Pharmaceuticals has developed novel inhibitors that interact with PSMA and may provide specific targeting for the detection, treatment and management of prostate cancer. Currently I-123-MIP-1072 is in clinical development as a specific molecular targeting agent to spatially localize and identify wide-spread disease. This proposal is designed to generate the pre-clinical efficacy data for the corresponding therapeutic I-131-MIP-1072 in order to assess the possibilities of developing the imaging agent into an effective treatment for prostate cancer.